Diagnosis and Management of Cerebral Venous Thrombosis: A Scientific Statement From the American Heart Association.

Cerebral venous thrombosis accounts for 0.5% to 3% of all strokes. The most vulnerable populations include young individuals, women of reproductive age, and patients with a prothrombotic state. The clinical presentation of cerebral venous thrombosis is diverse (eg, headaches, seizures), requiring a high level of clinical suspicion. Its diagnosis is based primarily on magnetic resonance imaging/magnetic resonance venography or computed tomography/computed tomographic venography. The clinical course of cerebral venous thrombosis may be difficult to predict. Death or dependence occurs in 10% to 15% of patients despite intensive medical treatment. This scientific statement provides an update of the 2011 American Heart Association scientific statement for the diagnosis and management of cerebral venous thrombosis. Our focus is on advances in the diagnosis and management decisions of patients with suspected cerebral venous thrombosis. We discuss evidence for the use of anticoagulation and endovascular therapies and considerations for craniectomy. We also provide an algorithm to optimize the management of patients with cerebral venous thrombosis and those with progressive neurological deterioration or thrombus propagation despite maximal medical therapy.

Birth Prevalence of Sickle Cell Disease and County-Level Social Vulnerability - Sickle Cell Data Collection Program, 11 States, 2016-2020.

Sickle cell disease (SCD) remains a public health priority in the United States because of its association with complex health needs, reduced life expectancy, lifelong disabilities, and high cost of care. A cross-sectional analysis was conducted to calculate the crude and race-specific birth prevalence for SCD using state newborn screening program records during 2016-2020 from 11 Sickle Cell Data Collection program states. The percentage distribution of birth mother residence within Social Vulnerability Index quartiles was derived. Among 3,305 newborns with confirmed SCD (including 57% with homozygous hemoglobin S or sickle ß-null thalassemia across 11 states, 90% of whom were Black or African American [Black], and 4% of whom were Hispanic or Latino), the crude SCD birth prevalence was 4.83 per 10,000 (one in every 2,070) live births and 28.54 per 10,000 (one in every 350) non-Hispanic Black newborns. Approximately two thirds (67%) of mothers of newborns with SCD lived in counties with high or very high levels of social vulnerability; most mothers lived in counties with high or very high levels of vulnerability for racial and ethnic minority status (89%) and housing type and transportation (64%) themes. These findings can guide public health, health care systems, and community program planning and implementation that address social determinants of health for infants with SCD. Implementation of tailored interventions, including increasing access to transportation, improving housing, and advancing equity in high vulnerability areas, could facilitate care and improve health outcomes for children with SCD.

Transcranial doppler velocity in iron-deficient Nigerian children with sickle cell anemia.

Oral iron supplementation in iron deficient children with sickle cell anemia and normal transcranial Doppler ultrasound (TCD) velocities does not reduce arterial flow in the middle cerebral artery.

Association of elevated tricuspid regurgitation velocity with cerebrovascular and kidney disease in children with sickle cell disease.

BACKGROUND: Tricuspid regurgitation velocity (TRV), measured by echocardiography, is a surrogate marker for pulmonary hypertension. Limited pediatric studies have considered the association between TRV and surrogate markers of end-organ disease. METHODS: We conducted a cross-sectional study that evaluated the prevalence of elevated TRV ≥2.5 m/s and its associations with renal and cerebrovascular outcomes in children with sickle cell disease (SCD) 1-21 years of age in two large sickle cell cohorts, the University of Alabama at Birmingham (UAB) sickle cell cohort, and the Sickle Cell Clinical Research and Intervention Program (SCCRIP) cohort at St. Jude Children's Research Hospital. We hypothesized that patients with SCD and elevated TRV would have higher odds of having either persistent albuminuria or cerebrovascular disease. RESULTS: We identified 166 children from the UAB cohort (mean age: 13.49 ± 4.47 years) and 325 children from the SCCRIP cohort (mean age: 13.41 ± 3.99 years) with echocardiograms. The prevalence of an elevated TRV was 21% in both UAB and SCCRIP cohorts. Elevated TRV was significantly associated with cerebrovascular disease (odds ratio [OR] 1.88, 95% confidence interval [CI]: 1.12-3.15; p = .017) and persistent albuminuria (OR 1.81, 95% CI: 1.07-3.06; p = .028) after adjusting for age, sex, treatment, and site. CONCLUSION: This cross-sectional, multicenter study identifies associations between surrogate markers of pulmonary hypertension with kidney disease and cerebrovascular disease. A prospective study should be performed to evaluate the longitudinal outcomes for patients with multiple surrogate markers of end-organ disease.

Barriers and Facilitators of Premarital Genetic Counseling for Sickle Cell Disease in Northern Nigeria.

In high-income countries, premarital genetic counseling for Sickle Cell Disease (SCD) is a standard practice. However, in Nigeria, there is no formal premarital genetic counseling program available for SCD. We conducted a series of focus group discussions with health care professionals, patients with SCD, and parents of the patients with or without SCD to gain an understanding of their attitudes and beliefs towards SCD/Sickle Cell Trait and premarital genetic counseling for SCD. Data were analyzed using Charmaz's constructivist grounded theory approach. Two themes were highlighted in the analysis as follows: (1) the difference between the perception of premarital sickle cell screening among individuals with SCD versus the general population, and (2) the personal beliefs and physical challenges that could lead to the avoidance of premarital screening within the general community. Lack of disease-related knowledge, testing facilities, transportation, and stigma associated with the disease were the most commonly perceived barriers to premarital testing. Also, a willingness to receive premarital testing for SCD exists within our community to reduce the spread of the disease and advocate for improved health-related quality of life of patients with SCD. The content and structure of a premarital genetic counseling program in Kano, Northern Nigeria, needs to be developed.

Factors associated with left ventricular hypertrophy in children with sickle cell disease: results from the DISPLACE study.

Cardiopulmonary complications remain a leading cause of morbidity and mortality in sickle cell disease (SCD). The overall goals of this study were to evaluate the relationship between left ventricular hypertrophy (LVH) and laboratory markers of hemolysis and determine the association between LVH and SCD-specific therapies (hydroxyurea and chronic red cell transfusion). Data from the DISPLACE (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) study cohort was used. LVH was defined based on the left ventricular mass indexed to the body surface area as left ventricular mass index >103.0 g/m2 for males and >84.2 g/m2 for females. There were 1,409 children included in the analysis and 20.3% had LVH. Results of multivariable analysis of LVH showed baseline hemoglobin levels were associated with the lower odds of having LVH (odds ratio [OR]: 0.71, 95% confidence interval [CI]: 0.60- 0.84). The odds of LVH increases for every 1-year increase in age (OR: 1.07, 95% CI: 1.02-1.13). Similarly, the odds of LVH were lower among males than females (OR: 0.59, 95% CI: 0.38-0.93). The odds of LVH were higher among those on hydroxyurea compared to no therapy (OR: 1.83, 95% CI: 1.41-2.37). Overall results of the study showed that LVH occurs early in children with SCD and the risk increases with increasing age and with lower hemoglobin. Further, we found higher use of hydroxyurea among those with LVH, suggesting that the need for hydroxyurea conveys a risk of cardiovascular remodeling.

Treatment-related Correlates of Growth in Children With Sickle Cell Disease in the DISPLACE Cohort.

Reduced growth and delayed maturation have been described in children with sickle cell disease (SCD). This study investigated growth and hemolysis in children with SCD in the DISPLACE (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) cohort. The database includes 5287 children, of which, 3305 had at least 2 growth measurements over a 5-year period. Body mass index was converted to z-scores (zBMI), and 19.8%, 66.1%, 14.2% of children were classified as underweight, normal, and overweight/obese, respectively. Multivariable analysis of growth was conducted and included variables: age, sex, blood pressure, hemoglobin, reticulocyte count, treatment with chronic red cell transfusion therapy (CRCT), or hydroxyurea therapy. Baseline hemoglobin levels were associated with the lower odds of being underweight (odds ratio [OR]=0.93, 95% confidence interval [CI]: 0.86-0.99), and higher odds of being overweight/obese (OR: 1.26, 95% CI: 1.17-1.36) compared with normal zBMI. CRCT was associated with being overweight/obese at baseline (OR: 1.85, 95% CI: 1.31-2.60). Overall, results showed that children who were underweight improved regardless of therapy over the 2-year time period. However, children on CRCT are at higher risk for being overweight and should be monitored closely.

Primary prevention of stroke in children with sickle cell anemia in sub-Saharan Africa: rationale and design of phase III randomized clinical trial.

Strokes in children with sickle cell anemia (SCA) are associated with significant morbidity and premature death. Primary stroke prevention in children with SCA involves screening for abnormal transcranial Doppler (TCD) velocity coupled with regular blood transfusion therapy for children with abnormal velocities, for at least one year. However, in Africa, where the majority of children with SCA live, regular blood transfusions are not feasible due to inadequate supply of safe blood, cost, and the reluctance of caregivers to accept transfusion therapy for their children. We describe the Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria Trial [StrokePreventioninNigeria (SPRING) trial, NCT02560935], a three-center double-blinded randomized controlled Phase III clinical trial to 1) determine the efficacy of moderate fixed-dose (20 mg/kg/day) versus low fixed-dose (10 mg/kg/day) hydroxyurea therapy for primary stroke prevention; 2) determine the efficacy of moderate fixed-dose hydroxyurea for decreasing the incidence of all cause-hospitalization (pain, acute chest syndrome, infection, other) compared to low fixed-dose hydroxyurea. We will test the primary hypothesis that there will be a 66% relative risk reduction of strokes in children with SCA and abnormal TCD measurements, randomly allocated, for a minimum of three years to receive moderate fixed-dose versus low fixed-dose hydroxyurea (total n = 220). The results of this trial will advance the care of children with SCA in sub-Saharan Africa, while improving research capacity for future studies to prevent strokes in children with SCA.

High Systolic Blood Pressure, Anterior Segment Changes and Visual Impairment Independently Predict Sickle Cell Retinopathy.

Sickle cell disease is often complicated by retinopathy, which can be proliferative or non proliferative. Proliferative sickle cell retinopathy potentially leads to blindness. There is a paucity of data on sickle cell disease-related retinopathy from Africa, where the disease is most prevalent. We aimed to determine the clinical, ophthalmic, and laboratory predictors of sickle cell retinopathy in an African population. We conducted a cross-sectional study of 262 participants, aged 13 years and above, with sickle cell disease. Demographic and clinical data were collected using a structured questionnaire and standard physical examinations. Vitreo-retinal specialists performed eye examinations on all the participants. Hematological and biochemical assessments were conducted using standard methods. A multivariate stepwise forward logistic regression was performed to determine the predictors of retinopathy. The median age of the participants was 20 years (interquartile range: 17-25 years). Most of the participants had a homozygous Hb S (HBB: c.20A>T) genotype (96.9%), with 3.1% who carried a Hb S/Hb C (HBB: c.19G>A) genotype. The prevalence of non proliferative sickle cell retinopathy was 24.4%. Only 1.9% had proliferative sickle cell retinopathy (PSCR). Elevated systolic blood pressure (BP) [odds ratio (OR): 6.85, 95% confidence interval (95% CI): 1.05-44.45, p = 0.059], moderate visual impairment (OR: 5.2, 95% CI: 1.39-19.63, p = 0.015), and anterior segment changes (OR: 2.21, 95% CI: 1.19-4.13, p = 0.012) were independently predictive of retinopathy. This study provides new insight into predictors of retinopathy in sickle cell disease, with implications on early screening and prevention.

Low educational level of head of household, as a proxy for poverty, is associated with severe anaemia among children with sickle cell disease living in a low-resource setting: evidence from the SPRING trial.

Severe anaemia, defined as haemoglobin level < 6·0 g/dl, is an independent risk factor for death in individuals with sickle cell disease living in resource-limited settings. We conducted a cross-sectional study of 941 children with sickle cell anaemia, who had been defined as phenotype HbSS or HbSß0 thalassaemia, aged five to 12 years, and were screened for enrollment into a large primary stroke prevention trial in Nigeria (SPRING; NCT02560935). The main aim of the study was to determine the prevalence and risk factors for severe anaemia. We found severe anaemia to be present in 3·9% (37 of 941) of the SPRING study participants. Severe anaemia was significantly associated with the lower educational level of the head of the household (P = 0·003), as a proxy for poverty, and a greater number of children per room in the household (P = 0·004). Body mass index was not associated with severe anaemia. The etiology of severe anaemia in children living with sickle cell anaemia in Nigeria is likely to be multifactorial with an interplay between an individual's disease severity and other socio-economic factors related to poverty.

How I treat and manage strokes in sickle cell disease.

Neurologic complications are a major cause of morbidity and mortality in sickle cell disease (SCD). In children with sickle cell anemia, routine use of transcranial Doppler screening, coupled with regular blood transfusion therapy, has decreased the prevalence of overt stroke from ∼11% to 1%. Limited evidence is available to guide acute and chronic management of individuals with SCD and strokes. Current management strategies are based primarily on single arm clinical trials and observational studies, coupled with principles of neurology and hematology. Initial management of a focal neurologic deficit includes evaluation by a multidisciplinary team (a hematologist, neurologist, neuroradiologist, and transfusion medicine specialist); prompt neuro-imaging and an initial blood transfusion (simple followed immediately by an exchange transfusion or only exchange transfusion) is recommended if the hemoglobin is >4 gm/dL and <10 gm/dL. Standard therapy for secondary prevention of strokes and silent cerebral infarcts includes regular blood transfusion therapy and in selected cases, hematopoietic stem cell transplantation. A critical component of the medical care following an infarct is cognitive and physical rehabilitation. We will discuss our strategy of acute and long-term management of strokes in SCD.

Feasibility trial for primary stroke prevention in children with sickle cell anemia in Nigeria (SPIN trial).

The vast majority of children with sickle cell anemia (SCA) live in Africa, where evidence-based guidelines for primary stroke prevention are lacking. In Kano, Nigeria, we conducted a feasibility trial to determine the acceptability of hydroxyurea therapy for primary stroke prevention in children with abnormal transcranial Doppler (TCD) measurements. Children with SCA and abnormal non-imaging TCD measurements (≥200 cm/s) received moderate fixed-dose hydroxyurea therapy (∼20 mg/kg/day). A comparison group of children with TCD measurements <200 cm/s was followed prospectively. Approximately 88% (330 of 375) of families agreed to be screened, while 87% (29 of 33) of those with abnormal TCD measurements, enrolled in the trial. No participant elected to withdraw from the trial. The average mean corpuscular volume increased from 85.7 fl at baseline to 95.5 fl at 24 months (not all of the children who crossed over had a 24 month visit), demonstrating adherence to hydroxyurea. The comparison group consisted of initially 210 children, of which four developed abnormal TCD measurements, and were started on hydroxyurea. None of the monthly research visits were missed (n = total 603 visits). Two and 10 deaths occurred in the treatment and comparison groups, with mortality rates of 2.69 and 1.81 per 100 patient-years, respectively (P = .67). Our results provide strong evidence, for high family recruitment, retention, and adherence rates, to undertake the first randomized controlled trial with hydroxyurea therapy for primary stroke prevention in children with SCA living in Africa.

Higher prevalence of wheezing and lower FEV1 and FVC percent predicted in adults with sickle cell anaemia: A cross-sectional study.

BACKGROUND AND OBJECTIVE: Respiratory symptoms including wheezing are common in adults with sickle cell anaemia (SCA), even in the absence of asthma. However, the prevalence of spirometry changes and respiratory symptoms in adults with SCA is unknown. METHODS: Using a cross-sectional study design, we tested the hypothesis that adults with SCA (cases) would have higher rates of lower airway obstruction and wheezing than those without SCA (controls) using the American Thoracic Society Division of Lung Diseases' questionnaire. Patients were adults with SCA aged between 18 and 65 years. Controls were consecutive unselected individuals without SCA who presented to an outpatient general medicine clinic. RESULTS: We enrolled 150 adults with SCA and 287 consecutive controls without SCA. The median age was 23.0 and 27.0 years for adults with and without SCA, respectively. Cases were more likely to report cough without a cold (35.0% vs 18.6%, P < 0.001), lower forced expiratory volume in 1 s (FEV1 ) % predicted (70.1% vs 82.1%, P = 0.001) and lower forced vital capacity (FVC) % predicted (67.4% vs 74.9%, P = 0.001) than controls. In the multivariable model, wheezing was significantly associated with SCA status (OR = 1.69, 95% CI = 1.08-2.65, P = 0.024). Similarly, FEV1 % predicted was significantly associated with SCA status and wheezing (P = 0.001 for both). CONCLUSION: Adults with SCA experience a higher rate of wheezing and impaired respiratory functions compared with controls from the same region.

PRIMARY STROKE PREVENTION IN CHILDREN WITH SICKLE CELL ANEMIA LIVING IN AFRICA: THE FALSE CHOICE BETWEEN PATIENT-ORIENTED RESEARCH AND HUMANITARIAN SERVICE.

In the United States, primary stroke prevention in children with sickle cell anemia (SCA) is now the standard of care and includes annual transcranial Doppler ultrasound evaluation to detect elevated intracranial velocities; and for those at risk, monthly blood transfusion therapy for at least a year followed by the option of hydroxyurea therapy. This strategy has decreased stroke prevalence in children with SCA from approximately 11% to 1%. In Africa, where 80% of all children with SCA are born, no systematic approach exists for primary stroke prevention. The two main challenges for primary stroke prevention in children with SCA in Africa include: 1) identifying an alternative to blood transfusion therapy, because safe monthly blood transfusion therapy is not feasible; and 2) assembling a health care team to implement and expand this effort. We will emphasize early triumphs and challenges to decreasing the incidence of strokes in African children with SCA.

Primary stroke prevention in Nigerian children with sickle cell disease (SPIN): challenges of conducting a feasibility trial.

BACKGROUND: The majority of children with sickle cell disease (SCD), approximately 75%, are born in sub-Saharan Africa. For children with elevated transcranial Doppler (TCD) velocity, regular blood transfusion therapy for primary stroke prevention is standard care in high income countries, but is not feasible in sub-Saharan Africa. PROCEDURE: In the first U.S. National Institute of Health (NIH) sponsored SCD clinical trial in sub-Saharan Africa, we describe the protocol and challenges unique to starting a clinical trial in this region. We are conducting a single arm pilot trial of hydroxyurea therapy in children with TCD velocity ≥200 cm/sec in the middle cerebral arteries. Eligible children will be placed on hydroxyurea (n = 40) and followed for 3 years at Aminu Kano Teaching Hospital, Nigeria. Adherence will be measured via the Morisky Scale and adverse events will be determined based on hospitalization. RESULTS: Originally, a randomized placebo trial was planned; however, placebo was not approved by the local Ethics Committee. Hence a single arm trial of hydroxyurea will be conducted and five controls per patient with normal TCD measurements will be followed to compare the rate of adverse events to those with abnormal TCD measurements taking hydroxyurea. Using non-NIH funding, over 9 months, multiple face-to-face investigator meetings were conducted to facilitate training. CONCLUSION: A hydroxyurea trial (NCT01801423) for children with SCD is feasible in sub-Saharan Africa; however, extensive training and resources are needed to build a global patient oriented multi-disciplinary research team with a common purpose.

Wheezing is common in children with sickle cell disease when compared with controls.

In children with sickle cell disease (SCD), wheezing may occur in the absence of asthma. However, the prevalence of wheezing in children with SCD when compared with children without SCD (controls) in the same setting is unknown. Using a case-control study design, we tested the hypothesis that children with SCD would have a higher rate of wheezing than those without SCD. We enrolled 163 children with SCD (cases) and 96 children without SCD (controls) from a community hospital in Nigeria. Parent reports of respiratory symptoms were identified based on responses to questions taken from the American Thoracic Society Division of Lung Diseases' Questionnaire. The median age was 8.5 years for children with SCD and 7.7 years for controls. Cases were more likely than controls to report wheezing both with colds (17.3% vs. 2.1%, P<0.01) and without colds (4.9% vs. 0%, P=0.03). Cases had 9.8 times greater odds of wheezing (95% confidence interval, 2.3-42.2). In the multivariable model, the only variable associated with wheezing was SCD status (odds ratio=18.7, 95% confidence interval, 2.5-142; P=0.005). Children with SCD experience a significantly higher rate of wheezing when compared with children of similar age without SCD.

Current Methods of Newborn Screening Follow-Up for Sickle Cell Disease Are Highly Variable and without Quality Assurance: Results from the ENHANCE Study.

Newborn screening (NBS) for sickle cell disease (SCD) has significantly improved childhood survival but there are still gaps resulting in delayed care for affected infants. As a state-run program, there are no national quality assurance programs to ensure each state achieves consistent, reliable outcomes. We performed this qualitative study of NBS follow-up practices to better evaluate and understand the multi-level, state-specific processes of how each state's public health department delivers the NBS results to families, how/if they ensure affected infants are seen quickly by sickle cell specialists, and to determine the close-out processes used in each state. This project used semi-structured interviews conducted with 29 participants across eight states to explore these NBS follow-up processes in each state. Participants included SCD providers, NBS coordinators, or personnel associated with state health departments and community-based SCD organizations (CBO). Our results show significant state-dependent variations in the NBS processes of information delivery and patient management. Specifically, programs differed in how they communicated results to affected families and which other organizations were informed of the diagnosis. There was also state-based (and intrastate) variation in who should assume responsibility for ensuring that infants receive confirmatory testing and are promptly started on penicillin prophylaxis. Case closure was also highly variable and poorly validated. Our results also yielded identifiable challenges and facilitators to NBS which were highly variable by state but potentially addressable in the future. This information suggests opportunities for systematic improvement in NBS follow-up processes.